Process for the production of chromone derivatives and intermediates produced thereby

ABSTRACT

This invention relates to a novel process for preparing chromone derivatives having the formula I:   wherein X represents hydrogen or lower alkyl; Y represents hydrogen, lower alkyl, or formyl, with at least one of X and Y being other than hydrogen; R1 represents hydroxy, lower alkyl, or lower alkoxy; R2 represents hydrogen, lower alkyl, or lower alkoxy; R3 represents hydrogen, lower acyl, or lower acyloxy; and wherein R1 and R2 together may form a methylenedioxy ring, by reacting a substituted phenol II with an acid anhydride III and a boron trifluoride compound, preferably boron trifluoride etherate, to provide a substituted 2,2-difluoro-4-lower alkyl1,3,2-benzodioxaborin intermediate IV and subjecting intermediate IV to treatment with a Vilsmeier reagent, such as phosphorus oxychloride together with dimethylformamide or phosphorus oxychloride together with dimethylacetamide, followed by hydrolysis. Certain of the final compounds I produced from the novel intermediates IV according to the process of this invention are useful as cardiovascular agents while others are useful in the treatment of allergic conditions and in the treatment of hyperacidity.

United States Patent [191 Kaminsky Oct. 14, 1975 [75] Inventor:

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Apr. 18, 1973 [21] Appl. No.: 352,133

Daniel Kaminsky, Parsippany, NJ.

[52] US. Cl 260/3405; 260/3455; 260/462 R; 424/282; 424/283; 424/298[51] Int. Cl. C07D 311/22; C07D 317/54 [58] Field of Search 260/3405,345.5, 462 R [56] References Cited OTHER PUBLICATIONS Durden et al., J.Org. Chem., Vol. 30, (1965), pp. 1684-1687.

VanAllen et al., J. Het. Chem., 2 6: 29-35, (Feb., 1969).

Reynolds et al., J. Het. Chem, 6: 375-377, (June, 1969).

Primary Examiner-James A. Patten Attorney, Agent, or FirmAlbert H.Graddis; Frank S. Chow; Anne M. Kelly [57] ABSTRACT This inventionrelates to a novel process for preparing chromone derivatives having theformula I:

wherein X represents hydrogen or lower alkyl; Y represents hydrogen,lower alkyl, or formyl, with at least one of X and Y being other thanhydrogen; R represents hydroxy, lower alkyl, or lower alkoxy; Rrepresents hydrogen, lower alkyl, or lower alkoxy; R representshydrogen, lower acyl, or lower acyloxy; and wherein R and R together mayform a methylenedioxy ring, by reacting a substituted phenol 11 with anacid anhydride I11 and a boron trifluoride compound, preferably borontrifluoride etherate, to provide a substituted 2,2-difluoro-4-1oweralkyl- 1 ,3 ,2-benzodioxaborin intermediate IV and subjectingintermediate 1V to treatment with a Vilsmeier reagent, such asphosphorus oxychloride together with dimethylformamide or phosphorusoxychloride together with dimethylacetamide, followed by hydrolysis.Certain of the final compounds I- produced from the novel intermediatesIV according to the process of this invention are useful ascardiovascular agents while others are useful in the treatment ofallergic conditions and in the treatment of hyperacidity.

13 Claims, 1 Drawing Figure PROCESS FOR THE PRODUCTION OF CI-IROMONEDERIVATIVES AND INTERMEDIATES PRODUCED TI'IEREBY SUMMARY OF THEINVENTION This invention relates to a novel process for preparingcompounds of the formula I:

wherein X represents hydrogen or lower alkyl; Y represents hydrogen,lower alkyl, or formyl, with at least one of X and Y being other thanhydrogen; R represents hydroxy, lower alkyl, or lower alkoxy; Rrepresents hydrogen, lower alkyl, or lower alkoxy; R representshydrogen, lower acyl, or lower acyloxy; and wherein R and R together mayform a methylenedioxy ring, which comprises treating a compound of theformula II:

with an acid anhydride of the formula III:

and a boron trifluoride compound, preferably boron trifluoride etherate,to provide an intermediate of the formula IV:

BRIEF DESCRIPTION OF THE DRAWINGS The novel process of the invention isillustrated schematically in FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION In FIG. I, the novel reaction ofthe instant invention and the novel intermediates and final productsproduced thereby are represented. A substituted phenol I is reacted withan acid anhydride II and a boron trifluoride compound to provide thenovel substituted intermediate IV which is reacted with a Vilsmeirreagent, followed by hydrolysis, to provide final compounds I.

The Vilsmeier reagent may be either phosphorus oxychloride (POCI withdimethylformamide (DMF) or phosphorus oxychloride (POCI withdimethylacetamide (DMA). The substituents obtained on final compound Idepend not only on the boron intermediate IV used, but also on thechoice of DMF or DMA. For example, if R, in the boron intermediate IV ishydrogen (i.e., the substituent in the 4-position is methyl) and DMF isused, a final compound I is obtained wherein X is hydrogen and Y isformyl, as in Examples XIV XXIV. With this same boron intermediate, whenDMA is used a final compound I is obtained wherein X is methyl and Y ishydrogen, as in Example XXVII.

Surprisingly, when R in the boron intermediate IV is methyl (i.e., the4-substituent is ethyl) and DMF is used, a final compound I is obtainedwherein X is hydrogen and Y is methyl, as in Example XXV. With this sameboron intermediate, when DMA is used a final compound I is obtainedwherein X is methyl and Y is methyl, as in Example XXVI.

The substituted phenol starting materials used in the novel process ofthis invention are readily available. The boron trifluoride compound ispreferably boron trifluoride etherate. The intermediate boron complex IVis novel and useful in the preparation of final compounds I which are,in turn, pharmacologically active.

Novel intermediates having formula IV above form an especially preferredgroup when R represents hydroxy, methyl, or methoxy; R representshydrogen, methyl, or methoxy; R represents hydrogen, acetyl, or acetoxy;wherein R and R together may form a methylenedioxy ring; and wherein R,represents hydrogen or methyl.

Compounds of the formula I wherein X and Y each represent hydrogen orlower alkyl (but where X and Y are not both hydrogen) and where R,, Rand R are hydrogen, have cardiovascular activity.

Compounds of the formula I wherein X is hydrogen, Y is formyl, and R Rand R are as previously described for formula I, have anti-allergic andantisecretory activity. Compounds within this group, which are picturedbelow in formula V, are more fully described in copending applicationSer. No. 352,149, filed Apr. 18, 1973.

CHO R 0 v wherein R represents hydroxy, lower alkyl, or lower alkoxy; Rrepresents hydrogen, or lower alkyl; and R represents hydrogen, loweracyl or lower acyloxy and wherein R and R together may form amethylenedioxy ring. Substituted 3-formylchromones of formula V havebeen found to reduce histaminic responses to antigen challenge byinhibiting antibody-antigen reactions in mammals such as rats or guineapigs upon oral or parenteral administration. When tested in accordancewith the procedure of Mota, Life Sciences, 7, 465, (1963) and Ovary,Proc. Soc. Exptl. Biol. Med., 81, 584, I952) therapeutic compositionscontaining these compounds are effective at dosages of 5 mg to 50 mg/kgof body weight.

Pharmaceutical compositions containing the compounds of formula V aretherefore useful in the management of allergic reactions such asbronchial asthma. To treat bronchial asthma, a dose of 5 mg to 50 mg/kgby injection or by aerosol administration is suggested. The dosage maybe varied depending upon severity of the condition and the weight, ageand sex of the patient being treated.

In use, the compounds of formula V may be combined with a parenterallyacceptable vehicle, such as a gum tragacanth saline suspension, toprovide dosage forms suitable for parenteral administration; or they maybe combined with pharmaceutical diluents such as lactonse, cornstarch,and the like formulated into tablet or capsule dosage forms. In order toenhance their therapeutic spectrum, the compounds of formula V may becombined with sympathomimetic agents such as isoprenaline or combinedwith steroids such as cortisone and its derivatives.

The compounds of formula V also exhibit antisecretory effects and aretherefore useful in relieving gastric hyperacidity. Gastric hyperacidityhas generally been described as a factor which contributes to pepticulcer. The compounds of formula V, when administered to mammals in amanner as described below, have been found to inhibit the gastricsecretion of hypochloric acid and are therefore effective in eliminatingthe resulting acidity in the stomach.

At a dosage of mg/kg, administered intraperitoneally the subjectcompositions are effective in reducing gastric acidity in the pylorusligated rate when tested according to the procedure of H. Shay,Gastroenterology, 5, 43, (1945 Pharmaceutical compositions containingthe compounds of formula V are thus indicated in the management ofgastric hyperacidity and the treatment of peptic ulcer resulting fromsuch hyperacidity. For parenteral administration, the pharmaceuticalcompositions containing the compounds of formula V may be administeredas aqueous suspensions for intramuscular injection. These are prepared,for example, by suspending the active ingredient in sterile water andpackaging in ampules so as to provide a concentration of 1,000 mg of theactive ingredient per dosage unit.

Generally speaking, the dose required to effectively relieve gastrichyperacidity is within the range of 20 mg/kg of body weight of themammal being treated. This dosage regimen may be varied depending uponthe condition of the patient.

In addition to the above-mentioned utilities, the intermediates of thisinvention having formula IV are useful for the preparation of othertherapeutically useful chromone derivatives, such as the correspondingcarboxylic acids, esters, nitriles, oximes or acetals.

An alternate method for preparing the intermediates IV, described inpart by Durden, J.A. et al., in J. Org. Chem. 30; 1684-1687 (1965),involves the reaction of 2-hydroxyacetophenone with acetic anhydride andboron trifluoride to provide 2,2-difluoro-4-methyl-1,3,2-benzodioxaborin. By subjecting this last mentioned compound toreaction with the Vilsmeir reagent, followed by hydrolysis, as taught bythe novel process of this invention, 3-formylchromone is obtained.

In all of the above formulas I, II, III, IV and V, R group and X and Ydefinitions may be more fully described as follows: the term lower alkylis meant to include lower aliphatic hydrocarbons having 1 to 4 carbonatoms in the carbon chain, such as methyl, ethyl, propyl, isopropyl,butyl, or isobutyl. This definition for lower alkyl also applies to thelower alkyl portion of lower alkoxy.

The term lower alcyloxy is meant to include lower alkyl carboxylic acidswherein the lower alkyl moiety has the above described meaning.Similarly, the term lower acyl is meant to include acyl groups derivedfrom such aforementioned lower alkyl carboxylic acids.

To further illustrate the practice of this invention, the followingexamples are included:

EXAMPLE I Method A Preparation Of 2,2-Difluoro-4-methyll ,3-dioxolo[4,5-g] 1,3,2-benzodioxaborin 100 g. (0.7 mole) of boron trifluorideetherate is added to a mixture of g. (0.5 mole) of sesamol (3,4-methylenedioxyphenol) in 204 g. (2 moles) of acetic anhydride. When theexothermic reaction subsides, the mixture is heated for 2 hours on asteam bath. The cooled mixture is diluted with 200 ml. of 1:1 ethylacetatezether and filtered. The crude, after ether washing and drying,weighed 102.7 g. (89.5%); mp 194-l97C. Recrystallization from ethylacetate gave bright yellow crystals, mp 198-200C.

Anal. Calcd. for C H BF O C, 47.42; H, 3.09; F. 16.67. Found: C, 47.43;H, 3.38; F, 16.50.

Preparation Of 2,2-Difluoro-7-methoxy-4-methyl-l ,3 ,2-benzodioxaborin2,2-Difluoro-7-methoxy-4-methyl-1 ,3,2-benzodioxaborin is prepared fromboron trifluoride etherate and m-methoxyphenol, accordingto theprocedure of Example to obtain a product having mp 173-174C.

6 Anal. Calcd. for C,,H,,BF O C, 50.52; H, 4.24; F of Example 1, toobtain a product having mp 17.76. Found C, 50.69; H, 4.46; F, 17.87.l38-140C.

Anal. Calcd. for C H BF O C, 49.23; H, 4.54; F, 15.57. Found: C, 49.27;H, 4.57; F, 15.75.

EXAMPLE m EXAMPLE VI Preparation Of6-Acetyl-2,2-difluoro-7-hydroxy-4-methyl-l,3,2-ben- OCH CH zodioxaborin3 3 6-Acetyl-2,2-difluoro-7-hydroxy-4-methyl-1 ,3 ,2- benzodioxaborin isprepared from boron trifluoride Pre aration of etherate and resorcinol,according to the procedure of 8 A I 2 2 h 4 h 1 3 Example I, to obtainaproduct having mp 197199C. cety I uoro' 9 'met y (dec). benzodioxabormAnal. Calcd. for C H BF O C, 49.64; H, 3.75; F,8-Acetyl-2,2-difluoro-5,7-dimethoxy-4-methyl-1,3,2- Foundibenzodioxaborin is prepared from boron trifluoride EXAMPLE Iv etherateand 3,5-dimethoxyphe nol, according to the procedure of Example 1, toobtain a product having mp 215217C. H CO 0 Anal. Calcd. for C, H BF O C,50.39; H, 4.58; F,

13.28. Found: C, 50.36; H, 4.52; F, 13.59. I 0+ EXAMPLE V H C 3Preparation Of 2,2-Difluoro-4-methyl-6,7-dimethoxy-1,3,2-benzodioxaborin 2,2-Difluoro-4-rnethyl-6,7-dimethoxyl,3,2-benzodioxaborin is prepared from boron trifluoride etherate and3,4-dimethoxyphenol, according to the procedure of Example I, to obtaina product having mp 219- Anal. Calcd. for 0, 11,350,: c, 49.23; H, 4.54;F, Preparam" of 1557. Found: C 4931; H F 15.85.8-Acetoxy-2,2-difluoro-7-methoxy-4-methyl-1,3,2-

benzodioxaborin X MPLE V E A8-Acetoxy-2,2-difluoro-7methoxy-4-methyl-1,3,2-

benzodioxaborin is prepared from boron trifluoride etherate and3-methoxycatechol, according to the procedure of Example I, to obtain aproduct having mp l73-175C (dec).

Anal. Calcd. for C H, BF O :C, 48.57; H, 4.08; I F,

13.97. Found: C, 48.47; H, 4.09; F, 14.16.

EXAMPLE Vlll Preparation Of 2,2-Difluoro-7,8-dimethoxy-4-methyl-1,3,2-benzodioxaborin 2,2-Difluoro-7,8-dimethoxy-4-methyl-1,3,2-benzodioxaborin is prepared from boron trifluoride etherate' and2,3-dimethoxyphenol, according to the procedure Preparation Of2,2-Difluoro-4-ethyll ,3-dioxolo[4,5-g] 1,3 ,2-benzodioxaborin isprepared from boron trifluoride etherate and 3,4-methylenedioxyphenol(sesamol) according to the procedure of Example I, using proprionicanhydride (instead of acetic anhydride), to obtain a product having mp162-164C.

Anal. Calcd. for C, ,H BF O C, 49.64; H, 3.75; F, 15.70. Found: C,49.58; H, 3.79; F, 15.71.

EXAMPLE 1X Method B Preparation Of 2,2-Difluoro-4-methy1-l,3,2-benzodioxaborin Boron trifluoride (170 g., 1.2 moles) is added to 82g. (0.6 mole) of o-hydroxyacetophenone. The mixture becomes quiteexothermic and is permitted to react for several hours. The cooledmixture is filtered, washed with ether and dried to yield 93g. (84.5%)of yellow crystalline solid; mp 139-141C. [Reported in J. Org. Chem 30:1684-1687 (1965) mp l42.5"l45"C.].

EXAMPLE X 1 Preparation Of2,2-Difluoro-4,6-dimethyl-1,3,2-benzodioxaborin 2,2-Difluoro4,6-dimethy1-1,3,2-be nzodioxabori n is prepared from boron trifluorideand 2'-hydroxy-5'- methyl-acetophenone according to the procedure ofExample IX, to obtain a product having mp 148l50.

Anal. Calcd. for C H BF O C, 54.60; H, 4.58; F,

19.19. Found: C, 54.21; H, 4.49; F, 18.49.

EXAMPLE XI Preparation Of2,2-Difluoro-5,7-dimethoxy-4-methyl-1,3,2-benzodi- 'oxaborin2,2-Difluoro-5,7-dimeth0xy-4-methyl-l ,3,2-benzodioxaborin is preparedfrom boron ,trifluoride and 2'- hydroxy-4,6'-dimethoxyacetophenoneaccording to the procedure of Example 1X, using ethyl acetate and Skellysolve. C (instead of ether), to obtain a product 10 having mp 154l55C.

Anal. Calcd. for C H,, BF O C, 49.23; H, 4.54; F, 15.57. Found: C,49.20; H, 4.57; F, 15.45. EXAMPLE X11 15 CH CFI Preparation Of2,2-Dif1uoro-4-ethyl-1 ,3,2-benzodioxaborin2,2-Difluoro-4-ethyl-1,3,2-benzodioxaborin is prepared from borontrifluoride and o-hydroxypropiophenone according to theprocedure ofExample 1X, to obtain a product having mp 1 161 18C.

Anal. Calcd. for C H BF O C, 54.60; H, 4.58; F, 19.19. Found: C, 54.40;H, 4.63; F, 19.24. 1 EXAMPLE X111 Preparation Of2,2-Difluoro-4,6,7-trimethy1 l ,3 ,2-benzodioxaborin2,2-Difluoro-4,6,7-trimethyl-1 ,3,2-benzodioxaborin is prepared fromboron trifluoride and 2-hydroxy-4,5-' dimethylacetophenone according tothe procedure of Example IX, to obtain a product having mp 189 l92C.

EXAMPLE XIV "11 C, CHO

Method C General Procedure And Preparation Of 3-formy1 6-methylchromoneA solution of Vilsmeier "Reagent is .prepared'by the moles). Thetemperature is maintained below 10C by use of a cooling bath. One-halfmole of the appropriate boron fluoride complex is added and the mixturestirred for minutes, then heated on a steam bath for 2 hours. Thereaction mixture is poured onto about 3 liters of cold water. Afterstanding at room temperature for several hours, the mixture is filteredto yield the desired substituted-3-formyl chromone derivative. Usingthis procedure, the following compounds are prepared:3-formyl-6-methylchromone is prepared from 2,2- difluoro-4,6-dimethyl-l,3,2-benzodioxaborin, according to procedure C, to obtain a producthaving mp l7l-l73C.

Anal. Calcd. for C H O C, 70.21; H, 4.29. Found: C, 69.95; H, 4.33.

EXAMPLE XV CHO Preparation Of 7-Methoxy-3-formylchromone7-Methoxy-3-formylchromone is prepared from 2,2-difluoro-7-methoxy-4-methyl-l ,3 ,2-benzodioxaborin, according toprocedure C of Example XIV, to obtain a product having mp 188-l90C.

Anal. Calcd. for C H O C, 64.70; H, 3.95. Found: C, 64.47 H, 4.09.

EXAMPLE XVI CHO Preparation Of 3-Formyl-6,7-dimethylchromone EXAMPLEXVII CHO Preparation Of 3-Formyl-5,7-dimethoxvchromone3-Formyl-5,7-dimethoxychromone is prepared from 2,2-difluoro-5,7-dimeth0xy-4-methyl-l ,3 ,2-benz0dioxaborin, according to procedure Cof Example XIV.

EXAMPLE xvm Preparation Of 3-Formyl-6,7-dimethoxychromone3-Formyl-6,7-dimethoxychromone is prepared from2,2-difluoro-4-methyl-6,7-dimethoxyl ,3 ,2-benzodioxaborin, according toprocedure C of Example XIV, to obtain a product having mp 222223C.

Anal. Calcd. for C, H, O C, 61.54; H, 4.30. Found: C, 61.54; C, 4.28.

EXAMPLE XIX OCH CH 0 3 Preparation Of 7,8-Dimethoxy-3-formylchromone7,8-Dimethoxy-3-formylchromone is prepared from2,2-difluoro-7,8-dimethoxy-4-methyl-I ,3,2-benzodioxaborin, according toprocedure C of Example XIV, to obtain a product having mp l8ll82C.

Anal. Calcd. for C H O C, 61.54; H, 4.30. Found: C, 61.44; H, 4.16.

EXAMPLE XX Preparation Of 3-Formyl-6,7-methylenedioxychromone3-Formyl-6,7-methylenedioxychromone is prepared from2,2-difluoro-4-methyl- I ,3-dioxolo[4,5-g] 1,3 ,2- benzodioxaborin,according to procedure C of Example XIV, to obtain a product having mp232233C.

Anal. Calcd. for C H O C, 60.56; H, 2.77. Found: C, 60.80; H, 2.79.

EXAMPLE XXI Preparation Of 8-Acetoxy-3-formyl-7-methoxychromone8-Acetoxy-3-formyl-7-methoxychromone is prepared from8-acetoxy-2,2-difluoro-7-methoxy-4- EXAMPLE XXII CI-IO Preparation Of6-Acetyl-3-formyl-7-hydroxychromone 6-Acetyl-3-formyl-7-hydroxychromoneis prepared from 6-acetyl-2,2-difluoro-7-hydroxy-4-methyl-l,3,2-benzodioxaborin, according to procedure C of Example XIV.

EXAMPLE XXIII Preparation Of 8-Acetyl-3-formyl-5,7-dimethoxychromone8-Acetyl-3-formyl-5,7-dimethoxychromone is prepared from8-acetyl2,2-difluoro-5,7-dimethoxy-4- methyl-l ,3,2-benzodioxaborin,according to procedure C of Example XIV.

EXAMPLE XXIV Preparation Of 3-Formylchromone EXAMPLE XXV Preparation Of3-Methylchromone A solution of Vilsmeier Reagent is prepared by slowaddition of 46 g. (0.3 mole) of phosphorus oxychloride to 110 g. (about1.5 moles) of cold dimethyl formamide, while maintaining temperaturebelow C.

After stirring for an additional 15 minutes, 30 g. (0.15

mole) of 2,2-difluoro-4-ethyl-l,3,2-benzodioxaborin is added and thenheated for 2 hours on a steam bath. The

mixture is poured into 2 liters of warm water. After several hours it isextracted with 3 X 250 ml. of chloroform. The combined chloroformextract is filtered through florisil, freed of solvent and the residuerecrystallized several times from high boiling petroleum ether to yield4.6 g, (19%) of almost colorless crystals of 3- methylchromone; mp -7lC.

,Anal. Calcd. for C H O C, 74.99; H, 5.03. Found: C, 74.87; H, 5.11..

EXAMPLE XXVI Preparation Of 2,3-Dimethylchromone To 26.1 g. (0.3 mole)of dimethylacetamide (cooled to about 0C) is added dropwise, 23 g. (0.15mole) of phosphorus oxychloride, with temperature maintained below 5Cduring addition. The solution is permitted to warm to room temperatureand 19.8 g (0.1 mole) of 2,- 2-difluoro-4-ethyl-l ,3,2-benzodioxaborinis added. The mixture is stirred for one hour and then heated for threehours on a steam bath. The mixture is poured into 2 liters of ice water.After standing overnight, the precipitated oil is separated and refluxedfor two hours with 500 ml. 5% hydrochloric acid. The cooled solution isextracted with methylene chloride. The combined methylene chlorideextracts are freed of solvent and the residue recrystallized severaltimes from Skellysolve B to yield lt. yellow crystalline product (20%);mp 9395C.

Anal. Calcd for C H O C, 75.84; H, 5.79. Found: C, 75.82; H, 5.96.

[Reported mp 96-97C, J. Ind. Chem. Soc., 39, 507 (1962)].

EXAMPLE XXVII Preparation of 6-Methyl-8H-l ,3-dioxol0[4,5g][ l]benzopyran-8-one 6-Methyl-8H-1,3-dioxolo[4,5-g][l]benzopyran- 8-one isprepared from 2,2-difluoro-4-methyll,3-dioxo[4,5-g]-l,3,2-benzodioxaborin according to the procedure of ExampleXXVI, to obtain a product having mp l77-1'7 8C. (dec).

Anal. Calcd. for O C HQ: C, 64.70; H, 3.95. Found: C, 64.68; H, 4.05.:

I claim:

l. A process for the preparation of a compound of the formula I:

wherein X represents hydrogen or lower alkyl; Y represents hydrogen,lower alkyl, or formyl, with at least one of X and Y being other thanhydrogen, R represents hydroxy, lower alkyl, or lower alkoxy; Rrepresents hydrogen, lower alkyl, or lower alkoxy; R representshydrogen, lower alkanoyl, or lower alkanoyloxy; and wherein R and R whenattached to adjacent carbon atoms, together may form a methylenedioxyring, which comprises treating a compound of the formula II:

with an acid anhydride of the formula III:

i (R CH CO) O [II and a boron trifluoride compound to provide anintermediate of the formula IV:

CHR

2. A compound of the formula IV:

wherein R represents hydroxy, or lower alkoxy; R represents hydrogen,lower alkyl, or lower alkoxy; R represents hydrogen, lower alkanoyl, orlower alkanoyloxy; and R, and R when attached to adjacent carbon atoms,together may form a methylenedioxy ring; and R represents hydrogen orlower alkyl.

3. A compound according to claim 2 wherein R represents hydroxy, ormethoxy; R represents hydrogen, methyl, or methoxy; R representshydrogen, acetyl, or acetoxy; and R and R when attached to adjacentcarbon atoms, together may form a methylenedioxy ring; and R representshydrogen or methyl.

4. A compound according to claim 3 which is 2,2-difluoro-4-methyl-l,3-dioxolo[4,5-g]1,3,2-benzodioxaborin.

5. A compound according to claim 3 which is 2,2- difluoro-7-methoxy-4-methyl-l ,3 ,Z-benzodioxaborin.

6. A compound according to claim 3 which is 6-acetyl-2,2-diflu0ro-7-hydroxy-4-methyl-l ,3,2-benzodioxaborin.

7. A compound according to claim 3 which is 2,2-difluoro-4-methyl-6,7-dimethoxy-l ,3 ,Z-benzodioxabo- 8. A compoundaccording to claim 3 which is 2,2- difluoro-7,8-dimethoxy-4-methyll ,3,2-benzodioxabo- 9. A compound according to claim 3 which is 8-acetyl-2,2-difluoro-5 ,7-dimethoxy-4-methyll ,3 ,2- dioxaborin.

10. A compound according to claim 3 which is 8-acetoxy-2,2-difluoro-7-methoxy-4-methyl-l ,3,2-benzodioxaborin.

11. A compound according to claim 3 which is 2,2- difluoro-4-ethyl-1,3-dioxolo[4,5-g]- l ,3 ,2-benzodioxaborin.

12. A compound according to claim 3 which is 2,2-difluoro-S,7-dimethoxy-4-methyl-I ,3,2-benzodioxaborin.

l3. aborin.

2,2-Difluoro-4,6,7-trimethyl-1,3 ,2-benzodiox-

1. A PROCESS FR THE PREPARATION OF A COMPOUND OF THE FORMULA I:
 2. Acompound of the formula IV:
 3. A compound according to claim 2 whereinR1 represents hydroxy, or methoxy; R2 represents hydrogen, methyl, ormethoxy; R3 represents hydrogen, acetyl, or acetoxy; and R1 and R2, whenattached to adjacent carbon atoms, together may form a methylenedioxyring; and R4 represents hydrogen or methyl.
 4. A compound according toclaim 3 which is2,2-difluoro-4-methyl-1,3-dioxolo(4,5-g)1,3,2-benzodioxaborin.
 5. Acompound according to claim 3 which is2,2-difluoro-7-methoxy-4-methyl-1,3,2-benzodioxaborin.
 6. A compoundaccording to claim 3 which is6-acetyl-2,2-difluoro-7-hydroxy-4-methyl-1,3,2-benzodioxaborin.
 7. Acompound according to claim 3 which is2,2-difluoro-4-methyl-6,7-dimethoxy-1,3,2-benzodioxaborin.
 8. A compoundaccording to claim 3 which is2,2-difluoro-7,8-dimethoxy-4-methyl-1,3,2-benzodioxaborin.
 9. A compoundaccording to claim 3 which is8-acetyl-2,2-difluoro-5,7-dimethoxy-4-methyl-1,3,2-dioxaborin.
 10. Acompound according to claim 3 which is8-acetoxy-2,2-difluoro-7-methoxy-4-methyl-1,3,2-benzodioxaborin.
 11. Acompound according to claim 3 which is2,2-difluoro-4-ethyl-1,3-dioxolo(4,5-g) -1,3,2-benzodioxaborin.
 12. Acompound according to claim 3 which is2,2-difluoro-5,7-dimethoxy-4-methyl-1,3,2-benzodioxaborin. 13.2,2-Difluoro-4,6,7-trimethyl-1,3,2-benzodioxaborin.